Details Of Published TSH Receptor Mutation
Ala 623 Val
c.1868C>TConstitutively Activating TSH Receptor Mutation
Type
gain
Manifestation
family
Exon
10
Pedigree 1 - Schwab et al.
Legend:
Male
Female
Unknown
Deceased
+
Mutation
-
No Mutation
Hyperthyroidism
(Heterozygous)
(Heterozygous)
Goiter
Relapse
P
Index Patient
Molecular Characteristics:
Pedigree 1: Schwab et al.
Clinical Features:
diagnosis:
I/2: 3yr (index patient)
II/1: 3.25 months
II/2: 3.5yr
* based on 21 hot nodules investigated by Paschke et al. 1994, Russo et al., 1996 Tonacchera et al. 1998, Fuhrer et al. 1997, Derwahl et al. 1996, Nogueira et al., 1999, Gozu et al. 2005 and 2006, Trulzsch et al. 2001, Palos-Paz et al. 2008, Krohn et al. 2008
and on 1 activating familial germline mutation investigated by Schwab et al. 1997
I/2: 3yr (index patient)
II/1: 3.25 months
II/2: 3.5yr
* based on 21 hot nodules investigated by Paschke et al. 1994, Russo et al., 1996 Tonacchera et al. 1998, Fuhrer et al. 1997, Derwahl et al. 1996, Nogueira et al., 1999, Gozu et al. 2005 and 2006, Trulzsch et al. 2001, Palos-Paz et al. 2008, Krohn et al. 2008
and on 1 activating familial germline mutation investigated by Schwab et al. 1997
Treatment:
I/2: antithyroid drugs, relapse after pause, 2 x partial TE, euthyroid
II/1, II/2: thiamazol+ L-thyroxine
II/1, II/2: thiamazol+ L-thyroxine
Functional Characteristics:
cAMP
(basal)
(basal)
cAMP
(TSH)
(TSH)
IP
(basal)
(basal)
IP
(TSH)
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
4.5-5.0
0.8-1.2
0.9-1.0
1.0
-
1.0
1
2,3
Legend:
cAMP (basal): basal in vitro cAMP production of mutant over wild-type TSHR
cAMP (TSH): maximal in vitro cAMP production of mutant over wild-type TSHR
IP (basal): basal in vitro IP production of mutant over wild-type TSHR
IP (TSH): maximal in vitro IP production of mutant over wild-type TSHR
TSH-binding: maximal TSH-binding compared to the wild-type TSHR
Cell surface expression: cell surface expression of mutant compared to WT-TSHR
LRA: linear regression analysis (LRA) of constitutive activity as a function of TSHR expression determined by 125I-bTSH binding or FACS analysis compared to the wild-type TSHR
Prevalence: Prevalence of (somatic and germline) activating mutations*
Ref: Reference for functional characterization
Child: Found in children.
Reference 1:
Schwab et al.
J. Pediatr. 131: 899-904
Constitutively active germline mutation of the thyrotropin receptor gene as a cause of congenital hyperthyroidism
1997
Reference 2:
Paschke et al.
J. Clin. Endocrinol. Metab. 79: 1785-1789
Identification and functional characterization of two new somatic mutations causing constitutive activation of the thyrotropin receptor in hyperfunctioning autonomous adenomas of the thyroid
1994
Reference 3:
Jäschke et al.
Cell Mol Life Sci 65:4028-4038
Preferences of transmembrane helices for cooperative amplification of G(alpha)s and G (alpha)q signaling of the thyrotropin receptor.
2008